The Efficacy and Safety of Deucravacitinib in Takayasu's Arteritis

Official title

Comparison of Deucravacitinib and Adalimumab for the Treatment of Relapsed Takayasu's Arteritis: The TYK-TAK Trial

Overview

This is a 24-week, single-center, randomized, open-label trial conducted by Peking Union Medical College Hospital. The aim of this study is to assess the efficacy and safety of deucravacitinib in adult patients with relapsing TAK in comparison to patients treated with TNF inhibitor (TNFi), the most well-recognized therapeutic choice of non-glucocorticoid immunosuppressive for patients with relapsed or refractory TAK.

Detailed description

Background:

The majority of patients with TAK experience relapses, and some patients fail to respond adequately to current medications used for treatment of TAK. There is an urgent unmet need to identify novel therapies to effectively treat TAK. Th-17 and Th-1 cells, and their related cytokines IL-12, IL-23, IL-17, and type I interferon have all been reported to play a role in the pathogenesis of TAK. Tyrosine kinase 2 (TYK2) mediates signaling transduction between these key cytokines and immune cells. Therefore, blocking TYK2 signaling may downregulate potential pathogenic pathways in TAK, and may be a therapeutic alternative. No study has investigated the effectiveness of agents targeting TYK2 in the treatment of TAK so far. In the present study, we aim to investigate whether deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, is effective and safe for patients with relapsed TAK.

Objectives:

To assess the efficacy and safety of deucravacitinib in adult patients with relapsing TAK in comparison to patients treated with TNF inhibitor (TNFi), the most well-recognized therapeutic choice of non-glucocorticoid immunosuppressive for patients with relapsed or refractory TAK.

Overall Design:

This is a 24-week, single-center, randomized, open-label trial conducted by Peking Union Medical College Hospital. Patients enrolled into the study are randomly assigned (in a 1:1 ratio, 25 patients in each group) to receive deucravacitinib or adalimumab (a TNFi). Patients are followed for efficacy and safety at month 1, month 3, and month 6. Adverse events/Serious adverse events are assessed and recorded at each visit.

Interventions

• Drug Deucravacitinib
  Deucravacitinib is a new, oral, selective, allosteric inhibitor of TYK2. It was first approved in the United States on 09-Sep-2022 for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
• Drug Adalimumab
  TNFα inhibitors have already been used in TAK treatment. Several retrospective studies have demonstrated the treatment effects of these agents in patients with TAK, including disease remission, GC tapering and vascular inflammation control. According to the ACR and EULAR guidelines, TNFis are recommended to be considered in cases of relapsing or refractory TAK. These agents (including adalimumab) are the most frequently analyzed therapeutic modalities in recent studies of TAK.

Primary outcome measures

• Overall response rate at week 24 [Time frame: Week 24]

Secondary outcome measures (8)

• Time to clinical remission [Time frame: from inclusion to the end of the study, 24 weeks in total]
• Disease recurrence after achieving clinical remission [Time frame: from inclusion to the end of the study, 24 weeks in total]
• Time to disease recurrence [Time frame: from inclusion to the end of the study, 24 weeks in total]
• Changes in erythrocyte sedimentation rate (ESR) [Time frame: week 4, 12 and 24]
• Changes in serum C reactive protein (CRP) [Time frame: week 4, 12 and 24]
• Changes in vascular ultrasonography [Time frame: from baseline to weeks 12 and 24]
• Changes in PET/CT scans [Time frame: from the baseline to week 24]
• Change in level of cytokines [Time frame: week 4, 12 and 24]

Eligibility criteria

Inclusion criteria

• Participants are eligible to be included in the study only if all of the following criteria apply:

• Signed Written Informed Consent

• Participants fully understand the purpose, nature, method, and possible adverse reactions of the study, willing to consent to the trial and follow study protocol and sign informed consent.
• Participants must have signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent form (ICF) in accordance with regulatory, local, and institutional guidelines. This ICF must be obtained before performing any protocol related procedures that are not part of normal patient care.
• Type of Participant and Target Disease Characteristics

• Adult patients (aged 18 or older) fulfilling the 2022 ACR/EULAR classification criteria for TAK.
• Persistence of active disease or relapse despite treatment with GCs combined with a conventional synthetic or biologics immunosuppressive agent other than TNFi.
• Active vasculitis by reader interpretation of FDG-PET at enrollment (by the same reader).
• Reproductive Status The investigator or designee shall counsel women of childbearing potential (WOCBP) and male participants who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy.

WOCBP must have a negative highly sensitive specify: urine or serum as required by local regulations pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study intervention.

A female is eligible to participate if she is not pregnant or breastfeeding and at least 1 of the following conditions applies:

Is not a WOCBP OR Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year) during the intervention period and for at least 5 half-lives after product administration and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period.

WOCBP and male participants who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception.

Exclusion criteria

• Participants are excluded from the study if any of the following criteria apply:

• Medical Conditions

• Severe disease from TAK for which urgent treatment with interventional procedures or bypass surgery is considered necessary
• Critical organ involvement of TAK, such as myocardial or coronary artery involvement, or cerebral ischemia
• Active hepatitis B or C virus infection, active tuberculosis infection
• Malignancy in the past 5 years (with the exception of fully excised non-melanoma skin cancer or cervical carcinoma in situ)
• Physical and Laboratory Test Findings

• Serum liver enzyme tests 3 times higher than the upper limits of normal range
• Estimated glomerular filtration rate ≤ 30 ml/minute
• Other Exclusion Criteria

• Females who are pregnant
• Ever treated with TNFi (including adalimumab) and discontinued due to inadequate response or intolerance.
• Any other sound medical, psychiatric, and/or social reason as determined by the investigator

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking Union Medical College Hospital — Beijing

Publications

• Le AM, Puig L, Torres T. Deucravacitinib for the Treatment of Psoriatic Disease. Am J Clin Dermatol. 2022 Nov;23(6):813-822. doi: 10.1007/s40257-022-00720-0. Epub 2022 Aug 12. PMID 35960487

Identifiers

NCT: NCT07013838 · TYK2-TAK-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗